Oral mucositis, a severe oral ulceration, is a common adverse effect of a large dose of radiation for bone marrow transplant or craniofacial radiotherapy for cancer. Severe oral mucositis could require feeding tubes, management of severe pain, and prematurely halting radiotherapy. Excessive inflammation and epithelial ablation are key features of oral mucositis.
Palifermin, a KGF (human keratinocyte growth factor) recombinant protein, is approved for preventing oral mucositis in bone-marrow transplant patients. Two Palifermin clinical trials in head and neck cancer patients showed that Palifermin reduced severe oral mucositis incidence from 67% and 69% to 51% and 54%, respectively. Other oral mucositis drugs in clinical trials or pre-clinical studies include growth factors, agents for radioprotection, anti-inflammatory agents or immune modulators.
The modest effects of Palifermin and drugs being developed in the above mentioned categories highlight the need for identification of biomarkers for novel therapies. However, the lack of routine diagnostic biopsies or discarded tissues from oral mucositis patients has hindered this effort.
Cutaneous wound healing progresses through three overlapping phases: inflammation, tissue formation, and tissue remodeling. These are dynamic processes that involve interactions among the epidermis, leukocytes, extracellular matrix (ECM), and dermal fibroblasts. In response to skin injury, blood clots, infiltrated inflammatory cells and other cell types in the wound release multiple cytokines and chemokines. These cytokines initiate fibroblast proliferation and synthesis of ECM that fill the wound deficit and lead to wound closure.
Meanwhile, keratinocytes at the wound edge begin to proliferate and migrate to cover the wound surface. Underneath the re-epithelialized epidermis, new stroma, called granulation tissue, begins to fill the wound space, which contains provisional ECM, inflammatory cells, fibroblasts, and blood vessels. Once the wound area is filled with the granulation tissue and covered by newly re-epithelialized epidermis, the process of wound closure is completed. Later on, the wound gradually returns to normal strength and texture through tissue remodeling.
Among the many molecules known to influence wound healing, transforming growth factor β (TGF-β) has the broadest spectrum of action, affecting all cell types that are involved in all stages of wound healing (Feng et al., Annu Rev Cell Dev Biol 21:659-693, 2005). The various functions of TGF-β are mediated by a number of signaling molecules, including the Smad family members. When a ligand binds to TGF-β type I and type II receptors (TGFβRI and TGF-βRII), TGF-βRI phosphorylates Smad2 and Smad3. Phosphorylated Smad2 and Smad3 bind a co-Smad, Smad4, to form heteromeric Smad complexes and translocate into the nucleus to regulate transcription of TGF-β target genes.
TGF-β signaling has been reported to exert both positive and negative effects on wound healing (Wang et al., J Investig Dermatol Symp Proc 11: 112-117, 2006). For instance, Smad3 deficient mice, in which TGF-β signaling is partially abrogated, exhibit accelerated wound healing (Ashcroft et al., Nat Cell Biol 1:260-266, 1999). In contrast, the introduction of exogenous Smad3 to wound sites to enhance TGF-β signaling also accelerated wound healing in a rabbit dermal ulcer model (Sumiyoshi et al., J Invest Dermatol 123:229-236, 2004). Skin wounds in Smad4-deficient mice have a dramatic increase in inflammation and angiogenesis causing a delay in wound closure and formed an excessive scar (Owens et al., Am J Pathol 176.122-133, 2010). Transient adenoviral gene transfer of Smad7, an antagonist of TGF-β signaling, in corneal epithelium and stroma resulted in accelerated corneal wound healing with reduced inflammation (Saika et al., Am J Pathol 166:1405-1418, 2005). Further, Smad7 gene transfer to the lens epithelium and stroma prevented injury-induced epithelial-mesenchymal transition of lens epithelial cells and suggests a potential role of Smad7 in prevention of capsular fibrosis (Saika et al., Lab Invest 84:1259-1270, 2004). However, adenoviral vector delivery of Smad7 to balloon injury in rat carotid arteries resulted in reduced vascular healing (Mallawaarachchi et al., Arterioscler Thromb Vasc Biol 25: 1383-1387, 2005). These studies suggest that the effects of TGF-β signaling components, such as Smad7, on wound healing are complex and highly context-specific. Additionally, the effect of Smad7 may not always be explained by its role in TGF-β signaling. For instance, Smad7 has also been shown to interact with components of the Wnt/β-catenin (Han et al., Dev Cell Biol 11:301-312, 2006) and the TNFβ/NF-κB (Hong et al., Nat Immunol 8:504-513, 2007) families.